While a dental student in Northern Ireland in the 1970s, Mark Ferguson became interested in the development of cleft palates. His curiosity led him to the swamps of Louisiana, Zimbabwe, and Australia to track alligators and crocodiles, whose palates develop in the same way that those of humans do (see BW, 5/16/05, "Britain: From Swamp Fox to Healer").
While operating on alligator embryos, the Belfast-born scientist made a chance discovery: The embryos' wounds healed scar-free. Thus began a 20-year quest to develop what he hopes will become the world's first prescription drugs to prevent and reduce scarring.
In 2000, he set up Renovo, a Manchester-based biotechnology company, with his partner and fellow Manchester University researcher, Sharon O'Kane. The mission: To apply his knowledge to treatments for humans. BusinessWeek London Correspondent Kerry Capell recently spoke to Ferguson about his research and its implications for a major unmet medical need. Edited excerpts of their conversation follow:
Q: Why has it been so difficult to develop an effective antiscarring treatment?
A:People thought scarring was an inevitable consequence of wounding. It's not. In the past, people have searched for drugs to accelerate wound healing. For instance, they focused on speeding up the healing of diabetic ulcers, pressure sores, or leg ulcers. But this is exceptionally difficult because the people with these wounds are already very sick. The failure to heal has to do with their underlying chronic disease.
We were the first people to develop pharmaceuticals to treat acute wounds such as those caused by cuts, surgery, and trauma -- not chronic wounds. In acute wounds, the mechanisms of scarring are more predictable.
It's a much bigger market opportunity as many more people have acute cuts than chronic wounds. And because the mechanisms of scarring are very similar in the skin, eyes, blood vessels, and nerves, we know that if a drug is successful in one area, it's also likely to be successful in another.
Q: You were studying cleft palate development in alligators and crocodiles when you made the discovery about scar-free healing. How did it come about?
A:We discovered scar-free healing by doing surgical experiments on alligator and mouse embryos. The discovery was completely accidental. We were creating a surgical model of cleft lip. We cut the lips of embryos while they were in the egg and found that, instead of developing a cleft lip, they healed perfectly without scars.
We discovered that transforming growth factor [TGF] Beta 3 [a naturally occurring protein in the body], which [constitutes] our lead drug, Juvista, is present in high levels in the embryo -- because it's involved in skin development -- and in low levels in adults.
By contrast, adult wounds have high levels of TGF Beta 1 and TGF Beta 2, and embryonic wounds have very low levels. That's because TGF Beta 1 and TGF Beta 2 come from inflammatory cells and from degranulating platelets when adult blood clots. Embryos have no blood clotting and fewer inflammatory cells. The ones they do have are less developed.
The differences between tissue repair with scarring and regeneration without scarring are quite subtle. For example, regeneration involves high levels of TGF Beta 3, while scarring involves high levels of TGF Beta 1 and TGF Beta 2. These differences can be manipulated with drugs.
Q: When people think of scarring, they tend to think of scarring to the skin. What are some of the complications caused by internal scarring?
A:Internal scarring following surgery or injury to your gut can cause significant pain and result in twisting of the guts that can be life-threatening. In the reproductive system, scarring in the fallopian tubes is a very common cause of infertility.
Q: Please explain the different drugs you're currently developing.
A:We have three drugs in Phase 2 human clinical testing. The lead drug is Juvista, or TGF Beta 3 protein, which is used anytime you bring the margins of wounds together. In the U.S., there are 42 million surgical procedures which do so every year. They include cosmetic and orthopedic surgeries, cesarean sections, and most accidents and emergencies.
Juvidex inhibits the activation of TGF Beta 1 and TGF Beta 2. It could be used to treat internal scarring such as scars to the gastrointestinal or reproductive tracts because it's a small molecule, so it's easier to deliver to internal organs. Juvidex can also be used in an eyedrop formulation for optical scarring following injury or laser surgery to correct vision.
Scarring is the most common complication from laser eye surgery. It can cause hazy vision, starbursts, and, at worst, make you partially or completely blind.
Q: What's the third drug?
A:Prevascar, which alters inflammatory response. This is a protein we're targeting especially to prevent scarring in nerves. If, for instance, you cut a nerve, the scarring by the two severed ends of the nerve prevents nerve reconnection, and you can lose either sensation or motor function. If you can prevent that scarring in animal models, you can facilitate nerve reconnection and hence restore sensory and motor function.
Q: What about scarring to the tissue around the heart?
A:There are two sorts of scarring in the heart. One is in the heart itself, where you get scar tissue after a heart attack. This causes abnormal function of the heart, which brings about a condition called cardiac hibernation, a reasonably common complication from heart attacks. We would target Juvidex for this indication because it's a small molecule.
The other problem is in blood vessels. So when you do surgery to join blood vessels, as in a cardiac bypass surgery, you get internal scarring that narrows the space for the blood to flow inside the vessel. This can restrict blood flow and, at worst, be life-threatening. We know that Juvista, or TGF Beta 3, is very effective in preventing the internal scarring in blood vessels in animal models. We will start clinical trials for scarring in bypass surgery this year.
Edited by Patricia O'Connell